Warfarin [3-(α-acetonylbenzyl)-4-hydroxycoumarin], a potent oral anticoagulant agent, is known to inhibit the enzyme vitamin K epoxide reductase (Whitlon et al., ref 18 b). The molecular mechanism of inhibition, however, is not known. It is proposed that the two major classes of oral anticoagulants, the 3-substituted-4-hydroxycoumarins and the 2-substituted- 1,3-indandiones, are mechanism-based inactivators of this enzyme. The proposed mechanism of inactivation involves enzyme-catalyzed activation of the oral anticoagulants by tautomerization to the hypothetically reactive diketo forms which then undergo attack by active-site nucleophiles. In order to test the chemistry of this proposal, it is shown that the two classes of oral anticoagulants are unreactive toward bases and nucleophiles (except for deprotonation), until they are electrophilically substituted at the 3 position of the coumarins or at the 2 position of the indandiones. These model compounds for the proposed enzyme-generated reactive intermediates, then, are shown to be highly reactive toward a variety of nucleophiles and support the hypothesis that the oral anticoagulants are converted by vitamin K epoxide reductase into reactive compounds which can acylate an active-site nucleophile and thereby inactivate the enzyme.
ASJC Scopus subject areas
- Colloid and Surface Chemistry